Neurofibromas in NF1: Schwann Cell Origin and Role of Tumor Environment

Abstract

Neurofibromatosis type 1 (NF1) is one of the most prevalent dominantly inherited genetic diseases of the nervous system. NF1 encodes a tumor suppressor whose functional loss results in the development of benign neurofibromas that can progress to malignancy. Neurofibromas are complex tumors composed of axonal processes, Schwann cells, fibroblasts, perineurial cells, and mast cells. Through use of a conditional (cre/lox) allele, we show that loss of NF1 in the Schwann cell lineage is sufficient to generate tumors. In addition, complete NF1-mediated tumorigenicity requires both a loss of NF1 in cells destined to become neoplastic as well as heterozygosity in non-neoplastic cells. The requirement for a permissive haploinsufficient environment to allow tumorigenesis may have therapeutic implications for NF1 and other familial cancers.

The Pathoetiology of Neurofibromatosis 1

“…76 The current understanding of the key role of Schwann cells is based on studies with conditional knockout mice and the genetic analysis of cells cultured from human neurofibromas. 32,76,77 These studies have collectively shown that bi-allelic inactivation of the NF1 gene is a prerequisite for neurofibroma formation but that tumorigenesis can occur only in an NF1 ϩ/Ϫ background. Neurofibromas can be classified into two main categories: cutaneous and plexiform.…”

“…The bi-allelic inactivation leading to the development of plexiform neurofibromas apparently takes place in embryonic cells that have the potential to generate large populations of cells carrying a single NF1 second-hit mutation. 77,81 The growth of plexiform neurofibromas during early childhood distinguishes these tumors from cutaneous neurofibromas, which are undetectable before puberty. 5 Mouse studies have demonstrated that Nf1 Ϫ/Ϫ Schwann cells are necessary, but not sufficient, for tumor formation to occur.…”

“…5 Mouse studies have demonstrated that Nf1 Ϫ/Ϫ Schwann cells are necessary, but not sufficient, for tumor formation to occur. Parada and coworkers 77 demonstrated that Nf1 flox/Ϫ ;Krox20cre mice, in which 5% to 10% of Schwann cells are nullizygous for Nf1 in an Nf1 heterozygous background, developed plexiform neurofibromas. In contrast, Nf1 flox/flox ;Krox20cre mice with both Nf1 alleles inactivated only in Schwann cells (other cells are wild type) failed to develop neurofibromas.…”

Role of infiltrated leucocytes in tumour growth and spread

“…Furthermore, Schwann cell tumours caused by inherited mutations in the NF1 gene do not form in mouse models unless the surrounding stromal cells are at least heterozygous for the mutation. These tumours are highly populated with mast cells and it seems likely that a haploinsufficiency of NFI in these cells is the cause of the tumour formation (Zhu et al, 2002).…”

The Development of Cutaneous Neurofibromas

“…It thus emerges that tumor progression requires complex interactions between Nf1 Ϫ/Ϫ Schwann cells and Nf1 ϩ/Ϫ cell lineages in the tumor microenvironment. 13 In this context, a recent study has shown that mouse Nf1 ϩ/Ϫ mast cells not only are recruited to neurofibromas from bone marrow but also that the neurofibromas fail to develop if the recruitment of the Nf1 ϩ/Ϫ cells is hindered, and the tumors begin to shrink when they are depleted of the Nf1 ϩ/Ϫ mast cells. 14 The present study points to the possible existence of yet another category of players in the development of cutaneous neurofibromas: multipotent NF1 ϩ/Ϫ precursor cells that can give rise to some of the different cell types found in neurofibromas.…”